Narita Takuhito, Yin Shaoman, Gelin Christine F, Moreno Carlos S, Yepes Manuel, Nicolaou K C, Van Meir Erwin G
Laboratory of Molecular Neuro-Oncology, Department of Neurosurgery, Winship Cancer Institute, Emory University, Atlanta, Georgia 30322, USA.
Clin Cancer Res. 2009 Oct 1;15(19):6128-36. doi: 10.1158/1078-0432.CCR-08-3180. Epub 2009 Sep 29.
Hypoxia inducible factor-1 (HIF-1), the central mediator of the cellular response to low oxygen, functions as a transcription factor for a broad range of genes that provide adaptive responses to oxygen deprivation. HIF-1 is overexpressed in cancer and has become an important therapeutic target in solid tumors. In this study, a novel HIF-1alpha inhibitor was identified and its molecular mechanism was investigated.
Using a HIF-responsive reporter cell-based assay, a 10,000-member natural product-like chemical compound library was screened to identify novel HIF-1 inhibitors. This led us to discover KC7F2, a lead compound with a central structure of cystamine. The effects of KC7F2 on HIF-1 transcription, translation, and protein degradation processes were analyzed.
KC7F2 markedly inhibited HIF-mediated transcription in cells derived from different tumor types, including glioma, breast, and prostate cancers, and exhibited enhanced cytotoxicity under hypoxia. KC7F2 prevented the activation of HIF-target genes such as carbonic anhydrase IX, matrix metalloproteinase 2 (MMP2), endothelin 1, and enolase 1. An investigation into the mechanism of action of KC7F2 showed that it worked through the down-regulation of HIF-1alpha protein synthesis, an effect accompanied by the suppression of the phosphorylation of eukaryotic translation initiation factor 4E binding protein 1 and p70 S6 kinase, key regulators of HIF-1alpha protein synthesis.
These results show that KC7F2 is a potent HIF-1 pathway inhibitor and its potential as a cancer therapy agent warrants further study.
缺氧诱导因子-1（HIF-1）是细胞对低氧反应的核心介质，作为多种基因的转录因子，可对氧剥夺产生适应性反应。HIF-1在癌症中过表达，已成为实体瘤的重要治疗靶点。在本研究中，鉴定了一种新型HIF-1α抑制剂并研究了其分子机制。
使用基于HIF反应性报告细胞的检测方法，对一个包含10000种天然产物样化合物的文库进行筛选，以鉴定新型HIF-1抑制剂。这使我们发现了KC7F2，一种以胱胺为核心结构的先导化合物。分析了KC7F2对HIF-1转录、翻译和蛋白质降解过程的影响。
KC7F2显著抑制源自不同肿瘤类型（包括胶质瘤、乳腺癌和前列腺癌）的细胞中HIF介导的转录，并在缺氧条件下表现出增强的细胞毒性。KC7F2可阻止HIF靶基因如碳酸酐酶IX、基质金属蛋白酶2（MMP2）、内皮素1和烯醇化酶1的激活。对KC7F2作用机制的研究表明，它通过下调HIF-1α蛋白合成起作用，这种作用伴随着真核翻译起始因子4E结合蛋白1和p70 S6激酶磷酸化的抑制，这两种蛋白是HIF-1α蛋白合成的关键调节因子。
这些结果表明KC7F2是一种有效的HIF-1通路抑制剂，其作为癌症治疗药物的潜力值得进一步研究。
